Progressive thickening, loss of elasticity, and occlusion of small and large blood vessels occurs as a part of the normal aging process with, or independently of, atherosclerosis. Because diabetes accompanies normal aging frequently, and shares many of the typical features of aging vasculopathy, it is accepted that its presence severely accelerates the effects of aging alone. Advanced Glycosylation Endproducts (AGE) are nonenzymatically glycosylated adducts of proteins accumulating in vascular tissues with aging, and at an accelerated rate in diabetes. The investigators have recently demonstrated that endothelial cells (EC) express a specific cell surface binding site for AGEs which, upon interaction with the ligand, mediates transcytosis of AGEs to the subendothelium, induces increased permeability and enhances EC pro-coagulant properties. These observations, in connection with the known abundance of AGEs in aged and diabetic vascular tissues, indicate that AGE-EC interactions may be crucial for the development of age and diabetes related vascular pathology. The objectives of this proposal are aimed at the elucidation of the response of vascular endothelium to AGEs by examining: 1) The nature of the AGE-binding site on endothelium, and its relationship to the recently identified AGE-receptor on macrophages. Purification of the receptor molecule, cloning of the receptor gene, and development of poly- and mono-clonal antibodies, and cloning of the receptor gene, will allow assessment of its functional properties and cell surface and tissue distribution. 2) The cellular processing and deposition of AGEs in subendothelial matrix. 3) The in vivo relevance of these observations, and their correlation to the progression of the diabetic and/or aging process, utilizing animal models. The first 2-3 years will be devoted largely to aims 1 and 2 while during the last two years the potential relationship of this system to in vivo relevant processes will be addressed. The interactions of this endothelial receptor with glucose-modified AGE-proteins may be biologically significant, as they involve a protein modification known to form abundantly in vivo. While the AGE-receptor system may normally function toward the selective disposal of modified macromolecules under conditions of enhanced tissue AGE accumulation, as it occurs in aging and diabetes, it may mediate vascular dysfunction, such as progressive occlusion, permeability and thrombotic diathesis, typically seen in the elderly and the diabetic patient.